Angina is a common indication of myocardial ischaemia either as a result of coronary artery disease or post acute myocardial infraction.
Verapamil (1) is presently in clinical use for the treatment of angina as a racemate. ##STR1##
The opposite enantiomers of verapamil have different biological activities and different potencies. The pharmacological profile is determined by stereoselectivity of pharmacodynamics and pharmacokinetics.
Satoh et al, Journal of Cardiovascular Pharmacology (1980) 2:309-318 disclose details of a study of the vasodilatory and cardiodepressant effects of the two enantiomers of verapamil. The authors report that a equieffective doses in terms of increasing coronary sinus outflow, (R)-verapamil is significantly less cardiodepressant than (S)-verapamil. They conclude from this that (R)-verapamil may provide a safer means of treating angina than (S)-verapamil, but add that it is not known which of the enantiomers of verapamil is of grater therapeutic value in the treatment of angina.
In reaching this conclusion the authors considered only two properties of verapamil, namely decrease in myocardial oxygen consumption and increase in coronary blood flow. The reduction in oxygen consumption was attributed to the negative inotropic action and negative chronotropic and hypotensive effects. The authors considered that the coronary vasodilator effect was most important for the anti-anginal action of verapamil, and cited nifedipine as a coronary vasodilator with a virtual lack of cardiodepressant action. However, coronary vasodilation is just one possible component, and certainly not the most important component, of the mechanism of treatment of angina. Accordingly, several compounds tried in the treatment of angina on the basis of their coronary vasodilatory action alone have failed in the clinic. This illustrates that the model utilised in the study by Satoh et al is not a true angina model. Accordingly, no reliance can be given to any conclusion based on that study.
Curtis et al. Proc. West. Pharmacol. Soc. (1986) 29:295-297 describe the use of a pithed rat preparation to evaluate the peripheral vasodilatory potencies of the different enantiomers of verapamil. Their study illustrated a potency difference of 23-fold in favour of (S)-verapamil as compared to (R)-verapamil. In a conscious rat model, however, they found a potency difference of 4-fold, again in favour of (S)-verapamil, for lowering blood pressure. This data is, in its own right, confusing, and when viewed alongside the data reported by Satoh et al, it is very difficult to predict the overall vasodilatory profile of (R)-verapamil, and accordingly whether it will have any meaningful therapeutic activity in the treatment of angina.
Consequently, it is not known which, if either, of the enantiomers of verapamil will be effective in the treatment of angina in the clinic.
A target profile of once a day therapy giving 24 hour control and protection from the symptoms of angina is sought, without the undesirable, dose-limiting side effects experienced with the racemate, eg. depression of myocardial contractility (see Satoh et al) and atrioventricular (AV) conduction block (see Raschack, Naunyn-Schmiedeberg's Arch. Pharmacol. (1976) 294:285-291).